There are a number of diseases known in humans that affect the joints, and particularly the synovium. These include synovial sarcomas, osteoarthritis, bacterial and fungal infections, and inflammatory, autoimmune, and hemorrhagic diseases. Combined, they are a cause of great pain and suffering in the population, with little effective therapy apart from symptomatic treatment with analgesics and anti-inflammatory drugs (reviewed by Gardner, 1994 J. Anat. 184:465-76).
Rheumatoid arthritis (RA) affects one percent of the population worldwide. There is significant immunological activity within the synovium during the course of the disease. It is believed that this reactivity provides an intense stimulus to the synovial lining cells, which then undergo a transformation into an invasive pannus that brings about joint erosion through the release of destructive mediators. The release of cytokines, proteases, and reactive oxygen intermediates, have all been implicated in the disease pathology. The initiating factor is unknown, but might be an infection, trauma, bacterial infection, or autoreactivity. For example, there is increased risk of developing rheumatoid arthritis for persons having the HLA-Dw4 allele.
Chronic rheumatoid arthritis is characterized by infiltration of the normally relatively acellular synovial membrane by macrophages, T cells, and plasma cells, and with the presence of activated fibroblast-like synoviocytes (Duke, O., et al, 1982, Clin. Exp. Immunol. 49:22-30). There are several reports in the literature which document the presence the cytokines of macrophage derivation including IL-1, IL-1.beta., IL-6, IL-8, IL-15, GM-CSF, and TNF-.alpha. in synovial proliferation. Cytokines associated with T cell activation such as IFN-.gamma., and IL-2 have also been detected in rheumatoid arthritis. The role of various cytokines and proteases in rheumatoid arthritis is discussed in Feldmann et al., 1994 Circ. Shock 43:179-84; and Testa et al, 1994 Clin. Orthop. 308:79-84. Therapies directed at T cells, such as cyclosporin A and monoclonal antibodies against T-cell surface antigens, can produce significant clinical improvement. However, additional therapies for rheumatoid arthritis are still needed.